Thalassemia is one of the most common genetic hemoglobinopathies that can result in severe anemia.1,2 It is highly prevalent in Southeast Asia, the Indian subcontinent and Mediterranean and Middle Eastern countries, collectively known as the ‘World Thalassemia Belt’. In Bangladesh, 6 to 12% of the population are carriers of a gene causing thalassemia.3 Thalassemia is characterized by the partial or complete deficiency in the synthesis of α or β-globin chains that compose the major adult hemoglobin (α2β2). Patients with an absolute deficiency of the α or β-globin chains require lifelong blood transfusion and are denoted as the transfusion-dependent thalassemia group.4 With regular transfusion, the life expectancy and survival rate of thalassemia patients dramatically improved from the first to fifth decades of life.5 However, it leads to iron overload, which is accumulated within different tissues, including endocrine glands, resulting in a functional imbalance, among which gonadal dysfunction is the most common.6,7 In addition to the iron overload, factors, such as ferritin level, genotype, transfusion frequency, starting age and iron chelation efficiency, also play a significant role.8 Hypogonadotropic hypogonadism, or secondary hypogonadism resulting from iron deposition in the pituitary gonadotrope, is more commonly found, whereas gonadal iron deposition in ovaries or testes occurs less frequently.9

In female patients, gonadal hormones, such as the luteinizing hormone (LH), estradiol, follicle-stimulating hormone (FSH), anti-mullerian hormone (AMH) and prolactin, are lower in transfusion-dependent thalassemia patients.7,10 Nearly half of these patients show a low to undetectable LH/FSH ratio.11 As a result, amenorrhea, anovulation and infertility are commonly found in adults. In younger females, the low gonadal function manifests as delayed puberty, delayed menarche or primary amenorrhea and short stature.12 In male patients, testicular functions are seen to be reduced, evidenced by the high anti-mullerian hormone and low testosterone levels.13 Lower sperm concentrations, a lower percentage of sperm with normal morphology, sperm DNA damage and reduced testis volume are also seen in transfusion-dependent thalassemia patients.14 The adult male clinical features are lack of facial and body hair, decreased muscle mass and appearance of fine facial wrinkles, gynecomastia, diminished libido, fatigue and ejaculatory dysfunction.15,16

Early assessment of gonadal dysfunction and its prompt treatment by chelation therapy may reduce its incidence, improve the quality of life in already burdened thalassemic patients and prevent further complications.17 Despite the high prevalence of thalassemia in our context, baseline information on gonadal function is not well addressed. Therefore, this study aimed to find the status of gonadal function in transfusion-dependent thalassemia patients and assess the role of the serum ferritin level in predicting hypogonadism.

The mean age of the participants was 18.81 ± 4.65 years, with the maximum being between 13 to 18 years of age (60.6%). There was a male (53.2%) preponderance, with a male-to-female ratio of 1.14:1. Most of the patients were from a rural area (57.4%) (Table 1).

The most common features of sexual underdevelopoment among males were long downy pubic hair (22%) (Tanner stage II) and testes 2.5 to 3.2 cm (Tanner stage II). In the case of females, the prominent features of sexual underdevelopment were long downy pubic hair (10%) (Tanner stage II) and breast-budding (25%) (Tanner stage II) (Table 2).

Among the 94 patients, the mean serum FSH of all patients was 4.52 ± 2.83 IU/L, of which the majority (89.36%) had a normal level of FSH and only 8.51% of the patients had an FSH below the normal level. Among the males, 4% had an FSH above the normal level, while none were below. Among females, 18.18% had an FSH below normal and none, above (Table 3). The mean serum LH of all the patients was 3.93 ± 2.82 IU/L, 11.70% having below the normal level of LH and the rest being within and above the normal. Among the males, 22% had an LH level above normal and 10%, below normal. Among the females, 13.64% had an LH below normal, while none were above normal. Among all the male patients, the mean serum testosterone was 390.29 ± 287.93 ng/dL, of which the majority (64%) had a normal testosterone level of and the rest (36%), below normal (Table 3). The mean serum estradiol of female patients was 85.05 ± 153.47 pg/mL, of which most (52.27%) had a normal level. Among the rest, 13.64% had above the normal level of estradiol and 34.09 %, below normal.

Hypogonadism was found in 33 patients (35.11%), afflicting 36% of all male and 34% of all female patients. Normogonadotropic hypogonadism, in 17 patients (18%), was the most prevalent type, followed by hypogonadotropic hypogonadism in 11 (12%) and hypergonadotropic hypogonadism in 5 (5%). The majority of the male patients with hypogonadism had the normogonadotropic type, found in 10 patients (20%); in contrast, the majority of the female patients with hypogonadism, 8 in all (18%), had the hypogonadotropic type. There was a significant difference in the distribution of the types of hypogonadism between males and females (p = 0.023) (Figure 2).

Figure 2.

Status of gonadal function among the study participants.

Pearson's chi-square test revealed significant difference in distribution of types of hypogonadism between males and females (p = 0.023).

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The mean serum ferritin level among the thalassemia patients was 2,665.51 (± 1,143.25) ng/ml. The serumferritin level was significantly higher (p < 0.001) in patients with hypogonadism (Eugonadal: 2,174.79 (±749.12) ng/ml; Hypogonadal: 3,572.59 (± 1,199.49) ng/ml) (Figure 3).

Figure 3.

Comparison of serum ferritin level in thalassemia patients with or without hypogonadism. Patients with hypogonadism had a significantly (p < 0.001) higher level of serum ferritin.

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Using receiver operating characteristic (ROC) curve analysis, a serum ferritin of 2,757 ng/ml was found to be the best threshold (Sensitivity = 69.70% and Specificity = 72.13%) for discriminating the presence of hypogonadism (Figure 4). The area under the curve (AUC) was high (0.83) and the p-value was highly significant (< 0.001). Both lower and upper bound areas were also above the area of 0.5, indicating that serum ferritin level could accurately predict hypogonadism.

Figure 4.

Receiver operating characteristic (ROC) curve for serum ferritin level.

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In the multiple logistic regression model, after adjusting for age and gender, patients with a serum ferritin level ≥ 2,757 ng/ml were eight times (AOR: 7.90, 95% CI: 2.63 to 23.69, p < 0.001) more at risk of developing hypogonadism, compared to those with a serum ferritin level < 2,757 ng/ml (Table 4).

In our study, the overall prevalence of hypogonadism was 35.11%, 18.1% being normogonadotropic, 11.7% being hypogonadotropic and 5.3% being hypergonadotropic. In a study among 21 male patients with transfusion-dependent beta-thalassemia (TDT), the prevalence of hypogonadotropic hypogonadism was 33.3%, which is consistent with our study.21 Furthermore, a cohort study in Taiwan among 454 TDT major patients showed a lower prevalence of hypogonadism (23.1%).22 Another study carried out by Daraghmeh et al., in the thalassemia ward at the AL-Wattani hospital in Nablus among 75 TDT patients, found that hypogonadism was prevalent among 46.7% of the tested patients, including both primary and secondary hypogonadism.23 However, the prevalence of hypogonadism in this study population was lower than some published reports,7,24–27 all of which have reported hypogonadism as the most frequent endocrinopathy among TDT patients from different countries. The availability of iron chelation therapy can explain the lower prevalence of hypogonadism in our study, compared to other studies. A study on 382 TDT patients treated with desferrioxamine at the Thalassemia Centre in Dubai showed a significantly lower prevalence of hypogonadism of only 25%.28 Moreover, chelation therapy with desferrioxamine before puberty has helped patients attain normal sexual maturation in some studies. In a study of 40 patients with TDT, 90% of 19 patients who began treatment with desferrioxamine before the age of 10 years had normal sexual development, compared to only 38% of those treated after the age of 10 years.29 However, results of a prospective study in patients with thalassemia and secondary amenorrhea suggest that the damage to the hypothalamus is progressive, despite regular transfusion and chelation therapy.30 These results suggest that the development of hypogonadotropic hypogonadism might be caused by early and progressive damage due to iron loading. We believe that these could be attributed to the possible progressive toxic effect of iron-induced free radicals and/or to some other undefined risk factors involved in the development of hypogonadotropic hypogonadism.31

There was no statistically significant relationship between gender and hypogonadism in our study. This result was similar to the studies carried out in Iran and Palestine.32,33 However, this result was different from the results of a study by Dumaidi et al., which stated that a higher percentage of hypogonadism in males indicates that males are more prone to hypogonadism than females.27

In the current study, serum testosterone, estradiol, LH and FSH were lower among 36%, 34.09%, 11.70% and 8.51% of the patients, respectively. The most common symptom of gonadal dysfunction among males was the lack of axillary and pubic hair (6%) (Tanner stage II) and among females, slow or absent breast growth, hot flashes and amenorrhea (6.82% each). Regarding the menstrual status, adult females presented hypogonadism in the form of total absence of spontaneous menarche (primary amenorrhea); this applied to 29% of female participants with TDT, as confirmed by the low level of estradiol. In contrast, the other form is the lack or irregular menses (secondary amenorrhea), found in 42% of female participants with TDT. In males, hypogonadism was in the form of sexual infantilism; this applied to 72% of male participants with TDT, which agrees with contemporary studies.34,35 Several other studies also revealed that, in the thalassemic group, the baseline and peak levels, after the GnRH test, of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and estradiol, were significantly lower than those in the control group.36,37 However, the discrepancy in the gonadotropin hormone level and gonadal dysfunction symptoms among males and females, compared to other studies, might be explained by ethnic factors, different availability of therapeutic agents and economic status.7

The transfusion-dependent beta-thalassemia (TDT) most often requires regular red blood cell transfusions, which start within the first year of life.38 The predilection for iron deposition in the pituitary gland and hypothalamus among these patients frequently causes a lack of sexual maturation and loss of gonadal function. Telfer et al. showed that the serum ferritin level is a relevant marker for the evaluation of iron overload.39 We found that hypogonadal patients had a significantly higher mean serum ferritin level, compared to eugonadal patients (Eugonadal: 2,174.79 (± 749.12) ng/ml; Hypogonadal: 3,572.59 (± 1,199.49) ng/ml). Patients with ≥ 2,757 ng/ml of serum ferritin level were almost eight times (AOR: 7.90, 95% CI: 2.63 to 23.69, p < 0.001) more at risk of developing hypogonadism, compared to those with a serum ferritin level < 2,757 ng/ml. This association between hypogonadism and serum ferritin level conforms to the existing evidence.40,41

In our study, approximately one-third of the TDT patients were found to be suffering from different hypogonadisms. Hypogonadal patients had a significantly higher serum ferritin level and the serum ferritin level was highly accurate in predicting hypogonadism. Therefore, the serum ferritin level, along with gonadal hormone analysis, of TDT patients can be considered a screening tool for assessing gonadal function and early detection and prevention of hypogonadism. However, further prospective studies with a larger sample size might be necessary to provide better recommendations for patients with TDT.